Para-aminosalicylic acid containing compositions



Patented Apr. 27,1954

; UNITED TATES PATENT OFFICE fiiR -iifiiiNosALIoYLIo .AGID CON- TAINING COMPOSITIONS Wiiliam P Bcger, iipper Darby, and l h a ries S. Miller,- Prospect Park, Pa., as's'ignorsto Merck & 00., Inc., a corporation of New Jersey Ndmawiiig'. Application February 24, 1951,

Serial No. 212,689

4 Claims; (Cl. 167-55) This invention relatesto new compositions Which are valuable in the administration of paraaminosalicylic acidin the therapy oftuberculosis.

A major difficulty in the, clinical application of para-aminosalicylic acid, hereinafter referred to as PAS, is that doses in excess of 8 to 12 grams per day induce nausea and gastrointestinal symptoms manifested by anorexia, vomiting and diarrhea in a majority of patients. These syruptoms make it nearly impossible to administer daily doses of to 24 grams that have been recommended in the treatment of this disease. As PAS is usually administered orally, the physical characteristics of the form in which the drug is given have some bearing on the patients tolerance, the hydrochloride being more irritating than the free para-amino'salicylic acid, and the latter being more irritating than its sodium salt. Thus, the attainment of higher plasma concentrations of PAS by the use of larger quantities of the free acid is impractical because of the gastrointestinal symptoms caused by large doses of the drug,- and, although the sodium salt of PAS is tolerated better, the drug in this form is more rapidly excreted. That PAS produces these symptoms because of local gastrointestinal irritation is substantiated by studies in which massive does of PAS have been administered intravenously for periods of up to six Weeks without the development of gastrointestinal symptoms even though plasma concentrations reached 40mg. per 100 m1.

Although it hasn'ot been definitely established that there is a direct corrlation' between the clinical course of tuberculosis treated with PAS and the plasma concentrations of PAS, it'seemed reasonable to strive for plasma concentrations of PAS in excess of the in vitro" sensitivity of the tubercle bacillus which ranges from as low as 0.015 mg. of PAS per 100 m1; of plasma to 1.53 mg. per 190 ml. for the more resistant strains of organism tested; Thus, it is recommended that concentrations ranging from 2 to '7 mg. of drug per 100 ml. of plasma, attainable when 10 to 14 gr. of PAS are administered dailyfbem-ainta'ined for satisfactory chemotherapy of this disease.

The problem of maintaining adequate plasma concentrations of PASi was" not easily solved since, as pointedout above; thf administration of larger daily doses or the drug cannot be re sorted to" because of the untoward patient reaction when a dose larger; than 8 to 12- gm. per day is administered; and since the intravenous administration" of the s um salt oi PAS im practical for the'extnde'd periods-of timeover culosis. I

which PAS is given in the treatment of tuber- The compositions pr this inventionfirovide a means for overcoming thefdifiicultie's hitherto experienced with the use of PAS because they make it possible to obtain elevated and prolonged plasma concentrations of the drugthus probably providing :an actual increase in the therapeutic e'fiicacy of PAS. Another advantage of the coinpositions of this invention isj t'ha t' they provide a means for'obtaining therapeutically effective plasma concentrations of PAS with greatly reduced dosage. Another important and practical value of this invention is the attai'n ment of these advantages by the use of anon-toxic compound which is efiective when given in small oral doses. I The compositions of the invention are com posite products including para-'aminosalicylic acid and the adjuvant, para-(di-n-prOpfi-sul famyD-benzoie acid; hereinafter referred to by the non proprietary chemical name, pjrobeneci'd.

Proben'ecid is prepared by the method described inCharlesS. Millers copending U. S. patent application Serial No. 162,811 new Patent No. 2,608,502 is'sued August 26,1953, of which the instant application is' in part a continuation The compound is a" crystalline, white powdery slightly soluble in water. It is absorbed rapidly from the'gastrointestinal tract; and after a singl oral dose; can be demonstrated in thep1asma of dogs for periods as long as about 36 hours and for about 24 hours in man. In the blood stream. the adjuvant is bound by adsorption to the plasma proteins to the extent of almost percent, and is excreted inth e' urine largely in a conjugated form, probably as a glucu'ro'ni'de. Extensive toxicologic and p-h armac'ologic studies established the fact that proben'ecid has a high therapeutic index. It. produces no toxic mani festations when administered oi ally or parenterally in humans or other animals in amounts large enough to inhibit the rapid ex'cr'etio'nof PAS. In mice, the oral L. D-sois 1, 156 vmg. per kg. of body weight, andwhen injected subcutane ously the L. D.sq is ,1,665 mg. per kg. ofbody Weight. Dogs have been closed with as much as 209 mg. per lig o f body weight! per day for as long as six weeks without significant toxicity, and human subjects have received 3 grains per day for 12 weeks, and 2 grams per day for 8 months without evidence of system toxicity.

The pharmacologic action of probenecid is believed to reside in its ability to inhibit'an enzymatic system which in activates PAS by con jugating it with glycine in which form it is rapidly excreted by way of the renal tubules. It has been found that PAS in unconjugated form is less readily excreted than in the conjugated form. Consequently, by preventing the conjugation of the drug, probenecid retards both the inactivation and elimination of PAS, and provides an increased and effective plasma concentration over a prolonged period of time. In this relation, probenecid may be thought to function as an anticatabolite.

Probenecid, administered together with or separately from PAS in a daily dose of about 1 to l grams, and advantageously in a daily dose of about 2 grams, increases the plasma concentrations of PAS from twoto four-fold. A single, oral dose of from 1 to 4 gm. of probenecid generally produces about a two-fold increase in the PAS plasma concentration, while the same quantity distributed over a twenty-four hour period, for example doses of 0.5 gr. every 6 hours, produces about a four-fold increase. Furthermore, these small quantities of probenecid maintain increased plasma concentrations of PAS, after a single dose, for as long as eight hours. Probenecid plasma concentrations as low as 2' to 6 mg. per 100 m1. produce measurable effects on the plasma concentration of PAS. Concentrations of this magnitude can be maintained by the administration of 1 gm. of adjuvant at 12 hour inter vals. While it has been demonstrated that 1 gm. of probenecid every 12 hours maintains a pharmacologic effect in man, the ei fect may not be optimal over this entire period in all patients, and the quantity of adjuvant administered must be adjusted accordingly. Probenecid thus offers the possibility of attaining therapeutic plasma concentrations of PAS even after the smaller doses of PAS that may be necessitated by reason of gastric intolerance of the patient to whom PAS is being administered. This increase in PAS plasma concentrations is observed whether the PAS is administered in the form of the free acid, its hydrochloride, or its sodium salt. However, it is preferred to administer the sodium salt of PAS because it is generally less irritating and more rapidly absorbed from the gastrointestinal tract than either the free acid orthe hydrochloride.

Examples illustrating the compositions of this invention are given below. It is to be understood, however, that the examples merely illustrate and do not limit the invention.

Example 1.C'0mpressed tablets Five thousand grams of para-aminosalicylic acid and 1,670 grams of probenecid were mixed together and then passed through a fin screen. The screened material was remixed and then granulated with about 150 cc. of a mixture composed of 2 parts corn starch paste (prepared by mixing 1 part of dry corn starch with 7 parts of water) and 1 part of a 20% gelatin solution. The moist granules were passed through a coarse screen, then spread thinly on trays and dried at 120 F. for about 18 hours. The dried material was reduced to a No. 14 granule. 644 grams of dry, sifted corn starch were intimately mixed with the granules, and finally a screened mixture of 150 grams of talc and 15 grams of magnesium stearate was added to the granulation and the composition was then compressed into tablets using one-half inch die standard curvature punches, yielding 10,000 tablets of 0.75 gram each, and each containing 0.5 gram of PAS and 0.167 gram of adjuvant.

4. Example 2.Gompressed tablets containing sodium PAS 5,000 grams of sodium para-aminosalicylate and 1,670 grams of probenecid were mixed together and then passed through a fine screen. The screened material was remixed and then granulated with about 400 cc. of corn starch paste prepared by mixing 1 part of dry corn starch with 7 parts of water. The moist granules were passed through a coarse screen, spread thinly on trays, and then dried in an oven at about F. for about 24 hours. The dried material was reduced to a No. 14 granule. 630 grams of dried, sifted corn starch were intimately mixed with the granules, and finally a screened mixture of grams of talc and 15 grams of magnesium stearat was added to the granulation and the composition was then compressed into tablets using one-half inch die standard curvature punches, yielding 10,000 tablets of 0.75 gram each, and each containing 0.5 gram sodium PAS and 0.167 gram of adjuvant.

Example 3.-C0mpresse0l tablets containing PAS hydrochloride 5,000 grams of para-aminosalicylic acid bydrochloride and 1,670 grams of probenecid were mixed together and then passed through a fine screen. The screened material was remixed and then granulated with about cc. of a mixture composed of 2 parts corn starch paste (prepared by mixing 1 part of dry corn starch with 7 parts of water) and 1 part of a 20% gelatin solution. Th moist granules were passed through a coarse screen, then spread thinly on trays and dried at 120 F. for about 18 hours. The dried material was reduced to a No. 14 granule. 644 grams or" dry, sifted corn starch were intimately mixed with the granules, and finally a screened mixture or" 150 grams of talc and 15 grams of magnesium stearate was added to the granulation and the composition was then compressed into tablets using one-half inch die standard curvature punches. yielding 10,000 tablets of 0.75 gram each, and each containing 0.5 gram of PAS hydrochloride and 0.167 gram of adjuvant.

Exampl 4.Efiervescent tablets 10,000 grams of para-aminosalicylic acid, 3,330 grams of probenecid, 9,790 grams of sodium bicarbonate and 80 grams of saccharin soluble were mixed together and then passed through a fine screen. The screened material was remixed and wetted with suificient acetone to permit its ready granulation in the usual Way. The moist granules were passed through a coarse screen, then spread thinly on trays and dried in an oven with circulating air at about 120 F. The dried material was reduced to a No. 12 granule, 4 fluid ounces of oil of peppermint were intimately admixed, and the composition was then compressed into tablets using 1 inch die flat face, beveled edge punches, yielding 10,000 tablets of 2.32 grams each, and each containing 1 gram of PAS and 0.333 gram of adjuvant.

Example 5.SoZuble elastic capsules 5,000 grams of para-aminosalicylic acid and 1,670 grams of probenecid were mixed together and then passed through a fine screen. The screened material was remixed and the mixture homogeneously dispersed in 3,330 grams of corn oil. The resulting composition was encapsulated in known manner in soft, elastic, sheet gelatin, hermetically sealed capsules, yielding 10,000 capsules, each holding 1 gram net of the composition and each containing 0.5 gram of PAS and 0.167 gram of adiuvant.

Example 6.-Soluble elastic capsules cont ining sodium PAS 5,000 grams of sodium para-aminosalicylate and 1,670 grams of probenecid were mixed together and then passed through a fine screen. 3,330 grams of corn oil were added gradually to the screened material and stirring continued until a homogeneous dispersion was obtained. The resulting composition was encapsulated in known manner in soft, elastic, sheet gelatin, hermetically sealed capsules, yielding 10,000 capsules, each containing 1 gram net of the composition and each containing 0.5 gram of sodium PAS and 0.167 gram of adjuvant.

Example 7.-Dry filled capsules 5,000 grams of para-aminosalicylic acid, 1,670 grams of probenecid, and 30' grams of dried corn starch were intimately and uniformly mixed, and the mixture filled into capsules, yielding 10,000 capsules each containing 0.67 gram of mixture containing 0.5 gram of PAS and 0.167 gram of adjuvant.

Example 8.-Dry, filled capsules containing sodium PAS 5,000 grams of sodium para-aminosalicylate, 1,670 grams of probenecid, and 30 grams of dry corn starch were intimately and uniformly mixed, and the mixture filled into capsules, yielding 10,000 capsules, each containin 0.6? grams net of the composition and each containing 0.5 gram of sodium PAS and 0.167 gram of adjuvant.

In the above examples where no particular specifications for individual ingredients are given, it is understood that there is used such quality of the various ingredients as is suitable for incorporation in pharmaceutical preparations.

Although each of the preceding examples contains probenecid as the adjuvant, any non-toxic, soluble salt of probenecid can be substituted for it.

The compositions of the invention can also include an antacid material, such .as aluminum hydroxide, magnesium trisilicate, trisodium citrate,

calcium carbonate, magnesium oxide, or other antacid substance suitable for administration for the purpose of neutralizing gastric acidity. The amount of antacid material is limited only to that which is desirable to use in connection with PAS or which can be physically incorporated in a tablet or capsule of suitable size for oral administration.

As to binders and lubricants used in making the tablets, such materials as lactose, corn starch, gum karaya, talc, calcium stearate, gelatin, ethyl cellulose, mineral oil, propylene glycol, glycerin, and the like, may be included in proportions commonly used in preparing tablets of this nature.

If the compositions are produced in the form of suspensions or solutions in an oleaginous material, there are available various substances which may be used for this purpose. Corn oil or other suitable oil can be used with advantage.

What we claim is:

l. A composite product prepared for therapeutic use, said product comprising a compound selected from the class consisting of para-aminosalicylic acid and non-toxic, therapeutically active salts thereof and an adjuvant selected from the class consisting of para-(di-n-propylsulfamyl) -benzoic acid and non-toxic, soluble salts thereof.

2. A composite product prepared for therapeutic use, said product comprising para-aminosalicylic acid and the adjuvant, para-(di-n-propylsulfamyl)-benzoic acid.

3, A composite product prepared for therapeutic use, said product comprising para-aminosalicylic acid, the adjuvant, para-(di-n-propylsulfamyl) -benzoic acid and sodium bicarbonate.

4. A composite product prepared for therapeutic use, said product comprising sodiumv paraaminosalicylate and the adjuvant, para-(di-npropylsulfamyl) -benzoic acid.

References Cited in the file of this patent -Iillson et al.: Federation Proceedings, vol. 9, No. 1, March 1950, page 320.

Bogen: American Review of Tuberculosis, February 1950, vol. 61, No. 2, pages 226-227, 234-235.

Manufacturing Chemist, April 1950, page 170, vol. XXI, No. 4. 

1. A COMPOSITE PRODUCT PREPARED FOR THERAPEUTIC USE, SAID PRODUCT COMPRISING A COMPOUND SELECTED FROM THE CLASS CONSISTING OF PARA-AMINOSALICYLIC ACID AND NON-TOXIC, THERAPEUTICALLY ACTIVE SALTS THEREOF AND AN ADJUVANT SELECTED FROM THE CLASS CONSISTING OF PARA-(DI-N-PROPYLSULFAMYL)-BENZOIC ACID AND NON-TOXIC, SOLUBLE SALTS THEREOF. 